Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

Abstract

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3.

Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing.

Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures.

Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

Figure. Family pedigrees, evolutionary conservation of the vesicular acetylcholine transporter (VACHT) receptor, and schematic structure

(A) Family pedigrees. (B) Evolutionary conservation of G186 and D398 in the 4th and 10th transmembrane domains. Conservation across species is shown on the top; conservation in orthologous genes is shown on the bottom. (C) Schematic diagram showing VACHT. The 12 transmembrane domains are shown. The Gly186Ala variant identified in patient 1 is shown in yellow in the fourth transmembrane domain. The Asp398His variant identified in patient 2 is shown in yellow in the 10th transmembrane domain. VMAT = vesicular monoamine transporter.